Transthyretin and BRICHOS: The Paradox of Amyloidogenic Proteins with Anti-Amyloidogenic Activity for Aβ in the Central Nervous System

Abstract

Amyloid fibrils are physiologically insoluble biophysically specific β-sheet rich structures formed by the aggregation of misfolded proteins. In vivo tissue amyloid formation is responsible for more than 30 different disease states in humans and other mammals. One of these, Alzheimer's disease (AD), is the most common form of human dementia for which there is currently no definitive treatment. Amyloid fibril formation by the amyloid β-peptide (Aβ) is considered to be an underlying cause of AD, and strategies designed to reduce Aβ production and/or its toxic effects are being extensively investigated in both laboratory and clinical settings. Transthyretin (TTR) and proteins containing a BRICHOS domain are etiologically associated with specific amyloid diseases in the CNS and other organs. Nonetheless, it has been observed that TTR and BRICHOS structures are efficient inhibitors of Aβ fibril formation and toxicity in vitro and in vivo, raising the possibility that some amyloidogenic proteins, or their precursors, possess properties that may be harnessed for combating AD and other amyloidoses. Herein, we review properties of TTR and the BRICHOS domain and discuss how their abilities to interfere with amyloid formation may be employed in the development of novel treatments for AD.

Inhibition of amyloid beta fibril formation by monomeric human transthyretin

“…48 The fact that monomeric TTR (as opposed to the genetically engineered constitutive monomer M-TTR used in this study) can inhibit fibril formation by Ab and possibly other amyloid precursors suggests that there may be a general ability for aggregation-prone proteins to interact in a heterotypic manner, whereas conformational specificity is required for nucleation and templating that leads to fibril formation via homotypic associations. 52 We conjecture that oligomers of M-TTR might display peptide structures that resemble Ab sequences to interfere with the specific interactions required for fibrils, generating aggregates that are less likely to form fibrils.…”

Apolipoprotein E impairs amyloid‐β fibril elongation and maturation

“…Proteolytic enzymes such as neprilysin and insulin‐degrading enzymes have been shown to degrade Aβ peptides and contribute to maintain a homeostatic Aβ concentration . A few proteins have also been identified as amyloid‐interfering molecules which can affect fibril assembly, examples of such proteins are transthyretin , proteins containing a BRICHOS domain , clusterin , and apolipoprotein E (ApoE) . In this context, the 34 kDa plasma protein ApoE is of specific interest due to its strong clinical impact on the development of AD .…”

Augmentation of Bri2 molecular chaperone activity against amyloid-β reduces neurotoxicity in mouse hippocampus in vitro

“…The BRICHOS domain has been found in several human precursor proteins, initially in Bri2, chondromodulin-1, and prosurfactant protein C (proSP-C) 28,29 . The BRICHOS domain has been suggested to prevent amyloid formation of aggregation prone regions (clients) of the respective proprotein during biosynthesis [30][31][32] . Recombinant human (rh) BRICHOS domains from proSP-C and Bri2 are efficient inhibitors also of amyloid formation of non-client proteins, such as medin, islet amyloid polypeptide (IAPP), Aβ40, and Aβ42 [33][34][35] .…”